TY - JOUR
T1 - Evidence for a stromal-epithelial "lactate shuttle" in human tumors
T2 - MCT4 is a marker of oxidative stress in cancer-associated fibroblasts
AU - Whitaker-Menezes, Diana
AU - Martinez-Outschoorn, Ubaldo E.
AU - Lin, Zhao
AU - Ertel, Adam
AU - Flomenberg, Neal
AU - Witkiewicz, Agnieszka K.
AU - Birbe, Ruth C.
AU - Howell, Anthony
AU - Pavlides, Stephanos
AU - Gandara, Ricardo
AU - Pestell, Richard G.
AU - Sotgia, Federica
AU - Philp, Nancy J.
AU - Lisanti, Michael P.
N1 - Funding Information:
It is now clear that both tumor cells and the surrounding stroma create the cancer microenvironment; however, previous studies have not examined whether these two cellular compartments are metabolically-coupled through a “lactate shuttle.” The “lactate shuttle” is a proposed mechanism for metabolically coupling cells within normal tissue; lactate produced via aerobic glycolysis in one cell is utilized by another cell to fuel oxidative mitochondrial metabolism. Examples of metabolically-coupled cells via the lactate shuttle are found in the brain between astrocytes and neurons, in the retinal Muller cells and F.S. and her laboratory were supported by grants from the W.W. Smith Charitable Trust, the Breast Cancer Alliance (BCA) and a Research Scholar Grant from the American Cancer Society (ACS). M.P.L. was supported by grants from the NIH/ NCI (R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660), and the Susan G. Komen Breast Cancer Foundation. A.K.W. was supported by a Young Investigator Award from the Breast Cancer Alliance, Inc., and a Susan G. Komen Career Catalyst Grant. R.G.P. was supported by grants from the NIH/NCI (R01-CA-70896, R01-CA-75503, R01-CA-86072 and R01-CA-107382) and the Dr. Ralph and Marian C. Falk Medical Research Trust. The Kimmel Cancer Center was supported by the NIH/NCI Cancer Center Core grant P30-CA-56036 (to R.G.P.). Funds were also contributed by the Margaret Q. Landenberger Research Foundation (to M.P.L.). This project is funded, in part, under a grant with the Pennsylvania Department of Health (to M.P.L. and F.S.). The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. This work was also supported, in part, by a Centre grant in Manchester from Breakthrough Breast Cancer in the UK (to A.H.) and an Advanced ERC Grant from the European Research Council.
PY - 2011/6/1
Y1 - 2011/6/1
N2 - Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to "feed" adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we cocultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal physiological function of muscle tissue and brain. These data are consistent with the "reverse Warburg effect," which states that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, "energy transfer" or "metabolic-coupling" between the tumor stroma and epithelial cancer cells "fuels" tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells. Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCT inhibitors.
AB - Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to "feed" adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we cocultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal physiological function of muscle tissue and brain. These data are consistent with the "reverse Warburg effect," which states that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, "energy transfer" or "metabolic-coupling" between the tumor stroma and epithelial cancer cells "fuels" tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells. Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCT inhibitors.
KW - Caveolin-1
KW - Lactate shuttle
KW - MCT1
KW - MCT4
KW - Metabolic coupling
KW - Monocarboxylic acid transporter
KW - Oxidative stress
KW - Predictive biomarker
KW - Pseudohypoxia
KW - SLC16A1
KW - SLC16A3
KW - Tumor stroma
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UR - http://www.scopus.com/inward/citedby.url?scp=79957922046&partnerID=8YFLogxK
U2 - 10.4161/cc.10.11.15659
DO - 10.4161/cc.10.11.15659
M3 - Article
C2 - 21558814
AN - SCOPUS:79957922046
SN - 1538-4101
VL - 10
SP - 1772
EP - 1783
JO - Cell Cycle
JF - Cell Cycle
IS - 11
ER -